Cells in the lung often migrate not as individual entities but as collective sheets, ducts, strands, or clusters. But how each cell can coordinate its migration with that of immediate neighbors has defied full comprehension. We propose here the hypothesis that a much overlooked but nonetheless central feature of coordinated cellular migration is that each constituent cell can become physically constrained (jammed) by nearest neighbors. The jamming hypothesis is deceptively simple, yet makes mechanistic predictions a priori that are surprising, complex, and testable. It predicts: 1) that a cell within the integrated monolayer cannot migrate without cooperative motions of its immediate neighbors;2) that this cooperativity retards system dynamics, and does so through spontaneous emergence of dramatically heterogeneous force chains that ripple through the system at multiple scales of organization;and 3) that decreasing adhesive interactions, or decreasing compressive stresses, or increasing tidal deformations as occur in breathing and mechanical ventilation, all serve to pro- mote cell unjamming and disaggregation, and are all described by a unified jamming phase diagram. Using a prototype of a unique experimental platform -Monolayer Stress Microscopy- we have obtained preliminary data supporting this novel physical picture. If it is shown to have predictive power, this hypothesis would bring together under one mechanistic rubric diverse aspects of collective sheet migrations in epithelial and endothelial monolayer physiology, as well as in repair, barrier function, fibrosis, and the epithelial-mesenchymal transition (EMT). PUBLIC HEALTH RELEVANCE: Recent technical and conceptual advances from our team1-13 lead to the suggestion that mechanics of the cellular monolayer in the lung, and in other organ systems as well, may be dominated by a change of state called the jamming transition. This new perspective leads logically to important new questions. In normal physiology, for example, do cellular monolayers tend to form solidlike aggregated sheets -with excellent barrier function and with little possibility of cell invasion or escape- because constituent cells are jammed? In pathophysiology, do certain cell populations become fluidlike and permissive of paracellular leak, transformation, invasion or cell escape because they become unjammed? To answer these questions, our interdisciplinary team will test the jamming hypothesis in well-characterized endothelial and epithelial monolayer systems. And to test the limits of applicability of the jamming hypothesis, we will study four well-characterized stable cell lines pre- and post-EMT. These experimental studies will be made possible by an enabling new technology that we pro- pose to develop: Monolayer Stress Microscopy.